Clonal hematopoiesis in monocytes contributes to HIV-associated neuroinflammation

单核细胞的克隆造血作用导致 HIV 相关的神经炎症

基本信息

批准号：
10675693
负责人：
SANJAY B. MAGGIRWAR
金额：
$ 47.26万
依托单位：
GEORGE WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-15 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10675693
关键词：
3-Dimensional Adhesions Affect Anti-HIV Agents Antibodies Blood - brain barrier anatomy Blood Platelets Blood Vessels Blood brain barrier dysfunction Brain Brain Diseases Cell Adhesion Molecules Cell Differentiation process Cells Central Nervous System Characteristics Chronic Circulation Clonal Expansion DNA Methylation DNA Modification Methylases Data Dioxygenases Endothelium Epigenetic Process Event Exhibits Exposure to Extravasation Gene Expression General Population Genes Goals HIV HIV Infections HIV Seronegativity HIV Seropositivity HIV-1 Hematopoiesis Heterogeneity Human Immune Impaired cognition Individual Infiltration Inflammatory Injury Integrins Intercellular adhesion molecule 1 JAK2 gene Learning Literature Macrophage Measures Mediating Modeling Monoclonal Antibodies Mus Myeloid Cells Nervous System Trauma Neurologic Neurologic Symptoms Neuronal Dysfunction P-Selectin P-selectin ligand protein Phenotype Physiological Play Process Promoter Regions Proto-Oncogene Proteins c-myc Role Secondary to Site Sorting Testing Tetanus Helper Peptide Time Vascular Cell Adhesion Molecule-1 Wild Type Mouse antiretroviral therapy astrogliosis axon injury brain endothelial cell cognitive ability demethylation experimental study gene product glial activation improved migration monocyte monolayer mouse model neuroinflammation neuroregulation novel promoter response shear stress

项目摘要

Summary Extravasation of inflammatory monocytes across the blood-brain barrier (BBB) in response to human immunodeficiency virus type-1 (HIV) is a critical event that leads to chronic neuroinflammation, neurologic injury, and subsequent loss of cognitive abilities in a significantly large number of infected individuals. However, given the heterogeneity of monocytes that exists in HIV-infected individuals receiving anti-retroviral therapy (ART), it remains unknown as to whether the neuro-modulatory actions of monocytes are limited to select subset of monocytes. Directly relevant to the goals of RFA-21-250, our supporting data reveals that the ART-treated HIV- infected individuals harbor higher numbers of inflammatory monocytes (CD14lowCD16hi) in their circulation. These cells also exhibit characteristic features of clonal hematopoiesis (CH), such as loss of DNA methyltransferase 3A (DNMT3A) and Tet methylcytosine dioxygenase 2 (TET2) with concurrent increase in the expression of janus kinase-2 (Jak2 ; these three gene products, and few others, are often termed as CH drivers). Interestingly, subsequent experiments in various models suggested that this monocyte subset (1) translocate to the central nervous system (CNS) in response to ART, in platelet-dependent manner, (2) is neuro-modulatory in action, and (3) can be expanded following exposure of monocytes to activated platelets and ART. Based on these findings, we posit that the priming of monocytes by activated platelets potentiates ART-mediated clonal hematopoiesis in monocytes, leading to HIV-associated neurologic injury. In this model, we propose that the composite effect of activated platelets and ART results into clonal expansion of inflammatory (CD14lowCD16hi) monocyte subset with CH, and subsequent demethylation/induction of PSGL-1 gene in them. Functionally, these events facilitate the transmigration of such monocytes into the perivascular spaces within the CNS, where these cells differentiate into macrophage phenotype, while retaining CH profile, and contribute to the neuronal dysfunction. This model then, in full accordance with the available literature, accounts for how neurologic manifestations are initiated and maintained due to immune-CNS interaction in ART-treated HIV- infected individuals.

概括响应人类的炎症单核细胞（BBB）的渗出免疫缺陷病毒类型1（HIV）是导致慢性神经炎症，神经系统损伤的关键事件并随后在大量受感染的个体中失去认知能力。但是，给予在接受抗逆转录病毒疗法（ART）的HIV感染者中存在的单核细胞的异质性关于单核细胞的神经调节作用是否仅限于选择子集仍然未知单核细胞。与RFA-21-250的目标直接相关，我们的支持数据表明，经过艺术治疗的HIV- 感染的个体在循环中具有更高数量的炎性单核细胞（CD14LOWCD16HI）。这些细胞还表现出克隆造血（CH）的特征，例如DNA的丧失甲基转移酶3A（DNMT3A）和TET甲基霉素双加氧酶2（TET2），并同时增加 Janus激酶2（JAK2；这三种基因产物以及其他几个基因的表达通常被称为CH驱动器）。有趣的是，随后的各种模型实验表明，该单核细胞子集（1）转移到中枢神经系统（CNS）以血小板依赖的方式响应ART，（2）是神经调节的单核细胞暴露于激活的血小板和艺术品后，可以扩展作用，并且（3）可以扩展。基于这些发现，我们认为通过激活的血小板启动单核细胞增强了Art介导的单核细胞中的克隆造血作用，导致与HIV相关的神经系统损伤。在这个模型中，我们提出激活血小板和ART的复合作用和炎症的克隆膨胀（CD14LOWCD16HI）带有CH的单核细胞子集，以及随后在其中PSGL-1基因的脱甲基化/诱导。从功能上讲，这些事件有助于将这种单核细胞移动到内血管周间空间中枢神经系统，这些细胞分化为巨噬细胞表型，同时保留CH轮廓，并有助于神经元功能障碍。然后，该模型完全根据可用文献说明了如何由于ART治疗的HIV - 受感染的人。